tbuckley/cabot-search huggingface dataset:
Immune response during regional chemotherapy.
Authors: Kornelia Aigner, Stephan Drothler, Karl R. Aigner, Karl R. Aigner
Journal: Journal of Clinical Oncology (2022)

e14537 Background: Regional chemotherapy is known to yield high drug concentrations in the treated tumor area while keeping systemic drug concentrations low. Regional Chemotherapy can be performed as an intra arterial infusion or isolated perfusion. Known perfusion techniques are isolated limb perfusion, hypoxic pelvic perfusion, hypoxic abdominal perfusion, upper abdominal perfusion, and isolated thoracic perfusion, Only little is known on the effect of chemotherapy on immune cells, especially not if chemotherapy is applied regionally. Since more and more immuno oncologic treatment possibilities arise, that often are combined with chemotherapy, knowledge on the effects on immune cells is crucial. Since systemic chemotherapy often decreases the number of immune cells in general, the more targeted approach of regional chemotherapy is investigated in this study. Methods: In this work, we investigate subpopulations of T-lymphocytes, Natural Killer cells and B-lymphocytes during regional chemotherapy and report on their changes after cycles of intra-arterial chemotherapy infusion followed by chemofiltration. Surface phenotyping of cells from EDTA blood was performed with combinations of monoclonal antibodies (anti- CD3,CD16, CD56, CD45, CD4, CD19, CD8, CD28, HLA-DR, CD39, CD25, CD127, CD45RA, CD45RO) for FACS analysis. 58 Patients with advanced breast cancer, ovarian cancer, head and neck cancer, lung cancer, or bladder cancer received regional chemotherapy as an intra arterial infusion therapy or an isolated perfusion therapy. Results: Contrary to the mild immune cell depletion during the first two cycles a more activated immune status is seen after treatment cycle three. Non-significant increase or stable numbers are observed for T-Lymphocytes and its subsets of CD4+ T-helper cells, CD8+ cytotoxic T-cells, and terminal memory T-cells (CD8+/CD28-/CD57+). Significant increase of cell numbers is observed for B-lymphocytes, regulative CD8+ T-cells (CD8+/CD28-/CD57-), activated HLA-DR+ T cells, and Natural Killer cells while regulative CD4+ T cells are significantly decreased. Conclusions: The data show that regional chemotherapy has controversial effects on the immune cell subpopulations. As every chemotherapy, it does affect immune cells, however to a limited extend, but importantly has an activating potential. Immune activation prevalently takes place after the third cycle of therapy which might be a hint for auto-vaccination caused by phases of repeated tumor necrosis after locally high drug concentrations. Finding the optimal dosage of chemotherapeutics may be crucial to balance direct tumor response, immune toxicity and immune activation.
EPEN-14. A Phase 1, Safety and Dose Escalation Study of BXQ-350 in Patients with Advanced Solid Malignancies Demonstrates that BXQ-350 is Well Tolerated and Shows Signs of Potential Clinical Activity in Ependymoma Patients
Authors: Olivier Rixe, John Morris, Robert Wesolowski, Emrullah Yilmaz, John Villano, Carolyn Muller, Trisha Wise-Draper, Vinay Puduvalli, Richard Curry III, Ray Takigiku, Gilles Tapolsky
Journal: Neuro-Oncology (2022)

Abstract The significance of a dysregulated sphingolipid metabolism in cancer, including brain tumors, has been demonstrated and several enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. Saposin C (Sphingolipid Activator PrO[S]etIN) is a human protein encoded by the Psap gene and is an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism. BXQ-350 is a nanovesicle of Saposin C that has broad anticancer activity, selectively inducing apoptosis of cancer cells by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations and inducing an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies including brain tumors (NCT02859857). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose, or the biological effective dose, of BXQ-350 administered intravenously at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and potential biomarkers. This trial was performed at four US sites. Results indicate that BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached. RANO or RECIST 1.1 criteria were used to evaluate tumor response. Analysis of plasma samples suggests that BXQ-350 modulates sphingolipid metabolism and impacts the immune system positively. Furthermore, potential signs of single agent activity were observed across tumor types, including in two ependymomas for which results will be presented.
The burden of long-term complications among adolescent and young adult cancer survivors: An international comparison of two large cohorts.
Authors: Samah Hayek, Gilad Libresco, Noam Barda, Chun Chao, Xu Lanfang, Kimberly L. Cannavale, Shai Izraeli, Saro Armenian
Journal: Journal of Clinical Oncology (2022)

e24059 Background: There is a paucity of information on health outcomes of adolescent and young adult (AYA) cancer survivors outside of Northern Europe or North America. We compared long-term health outcomes of Israeli AYA cancer survivors to non-cancer individuals with similar demographics and access to healthcare, estimated the risk of developing chronic health conditions by cancer type, and compared the comorbidity burden in Israeli AYA survivors to AYA cancer survivors from the U.S. Methods: This was a retrospective cohort of 2-year cancer survivors diagnosed with invasive cancer between 15 to 39 years of age from 2000 to 2018 in Clalit Health Services (CHS), the largest payer-provider healthcare organization in Israel. Non-cancer CHS participants were matched 4:1 to cancer survivors on age, sex, ethnicity, and membership duration. Health conditions were limited to those requiring medical intervention. Incidence rates for health conditions were determined for the two cohorts, and Poisson regression was used to determine the incidence rate ratio (IRR) with associated 95% confidence intervals (CI). A sub-population of CHS AYA survivors was used to compare the incidence of chronic health conditions from the Israeli cohort to AYA cancer survivors from Kaiser Permanente Southern California (KPSC), using Standardized Incidence Rate (SIR). Results: There were 12,674 CHS AYA cancer survivors and 50,696 non-cancer participants. Among survivors, the mean age at diagnosis was 31.02 years (SD: 6.2), 61.7% were female, and 78.4% were Jewish. The most common cancer diagnoses were lymphoma (16.5%), breast (16.4%), and thyroid (14.0%). Cancer survivors were significantly more likely to have any (IRR 1.60 95%CI: 1.54-1.67) or multiple (IRR 1.82 95%CI: 1.72-1.94) chronic health conditions compared to non-cancer participants. Survivors had an increased risk across nearly all examined outcomes, with an especially higher risk for premature ovarian failure (IRR 6.02 95%CI: 2.14-16.91), osteoporosis (IRR 4.74 95%CI: 4.06-5.53), and cardiomyopathy (IRR 4.20 95%CI: 3.35-5.27). We also found clear differences in the risk of specific health conditions by cancer type. Compared to the KPSC cohort, CHS cancer survivors had an overall lower (SIR 0.82 95%CI: 0.79-0.84) incidence of developing any health condition, with noticeably lower incidences of hypertension, hyperlipidemia, chronic liver disease, but higher incidences of cardiopulmonary diseases and osteoporosis. Conclusions: AYA cancer survivors in Israel are at increased risk for developing chronic conditions, compared matched non-cancer individuals, but the overall incidence of was lower when compared to survivors living in the U.S. These findings may allow for refinement of surveillance recommendations for AYA survivors, taking into consideration regional differences in socio-demographics and cancer care.
Assessment of effectiveness of neoadjuvant chemotherapy in patients with resectable gastric cancer.
Authors: Veronika Patsko, Andrii Lukashenko, Yuriy Ostapenko
Journal: Journal of Clinical Oncology (2022)

e16006 Background: Despite a sharp decrease in gastric cancer (GC) incidence, it remains one of the most common cancers in Ukraine as well as the whole world. According to big data from randomized trials that was analyzed, neoadjuvant chemotherapy (CT) was one of the most effective options. This study was performed to assess the effectiveness and safety of neoadjuvant chemotherapy among patients with resectable gastric cancer. Methods: 73 patients with resectable gastric cancers were randomized in two groups: group A (n = 38) who underwent neoadjuvant chemotherapy (with FLOT scheme) followed by planned surgery and group B (n = 35) for whom only surgery was performed. Data was collected in the clinic of National Cancer Institute from 2011 to 2017. Primary endpoints were overall survival (OS), progression free survival (PFS) and biological marker evaluation. Results: Molecular marked VEGFR-1 was found to correlate with cancer tumor cells sensitivity to chemotherapy. There was no significant difference in 5-year OS (55.2% in group A and 57.1% in group B respectively, p = 0.18). There was also no significant difference in PFS between two groups (32.6 month vs 33.1 month respectively). Conclusions: this study showed that there is no significant difference for OS and PFS in patients with resectable gastric cancer whether they received neoadjuvant CT or not. But it was found that there molecular markers such as VEGFR-1 could be used as a predictors for tumor response on systemic treatment. Determination of sensitivity to neoadjuvant CT helps to avoid useless toxicity and offers reducing the overall cost of treatment.
Identifying common concerns and predicting vulnerable populations among breast cancer survivors.
Authors: Pooja Roy, Iuliia Kovalenko, Janet Chan Gomez, Beth Rudge, Yijin Wert, Lisa Torp, Yijin Wert
Journal: Journal of Clinical Oncology (2022)

e24064 Background: Long-term survival is common after breast cancer treatment with 5-year survival reaching almost 90%. Breast cancer survivors (BCS) face varying degrees of quality of life (QOL) issues depending on their age of diagnosis, disease severity, and treatment. We present a retrospective analysis aimed to describe demographics of BCS, recognize common concerns and identify the vulnerable patients. Methods: This is a retrospective analysis of BCS seen at our Breast Cancer Survivorship Program from October 2016 to May 2021. Patients were given a survey to assess self-reported symptoms following treatment. The descriptive analysis of patient characteristics included age, cancer stage, and treatment type. The bivariate analysis included the relationship between the patient characteristics and their outcomes. Chi-square test was used to analyze group differences. Fisher exact test was employed when any of the expected frequencies was five or less. Logistic regression models were developed to identify significant predictors for outcomes. Results: 902 patients (age 26-94; median 64) were seen. Patient's characteristics studied included cancer stage, age group, and treatment modality. Most common self-reported concerns affecting BCS were fatigue (34%), insomnia (33%), hot flashes (26%), night sweats (23%), pain (22%), trouble concentrating (19%) and neuropathy (21%). Majority of patients (91%) reported having a happy outlook and felt a sense of purpose (89%), but 13% of BCS felt isolated at least 50% of the time. Young survivors (age ≤45) (p = 0.028), higher stage BCS (Stage 2-3) (p = 0.0061) and those who had chemotherapy either alone or as part of their multi-modality treatment (p &lt; 0.0001) were significantly less likely to return back to at least 50% of their pre-treatment baseline (Table). Conclusions: Our study showed that younger BCS, patients with higher cancer stage, and those who underwent chemotherapy are the most vulnerable groups in terms of severity of QOL issues. Identifying vulnerable populations and evaluating common concerns after treatments are important in delivering quality care. Optimizing interventions under standardized approach would help to increase QOL in BCS.[Table: see text]
Prospective Comparison of Medical Oncologists and a Machine Learning Model to Predict 3-Month Mortality in Patients With Metastatic Solid Tumors
Authors: Finly J. Zachariah, Lorenzo A. Rossi, Laura M. Roberts, Linda D. Bosserman
Journal: JAMA Network Open (2022)

To date, oncologist and model prognostic performance have been assessed independently and mostly retrospectively; however, how model prognostic performance compares with oncologist prognostic performance prospectively remains unknown.To compare oncologist performance with a model in predicting 3-month mortality for patients with metastatic solid tumors in an outpatient setting.This prognostic study evaluated prospective predictions for a cohort of patients with metastatic solid tumors seen in outpatient oncology clinics at a National Cancer Institute-designated cancer center and associated satellites between December 6, 2019, and August 6, 2021. Oncologists (57 physicians and 17 advanced practice clinicians) answered a 3-month surprise question (3MSQ) within clinical pathways. A model was trained with electronic health record data from January 1, 2013, to April 24, 2019, to identify patients at high risk of 3-month mortality and deployed silently in October 2019. Analysis was limited to oncologist prognostications with a model prediction within the preceding 30 days.Three-month surprise question and gradient-boosting binary classifier.The primary outcome was performance comparison between oncologists and the model to predict 3-month mortality. The primary performance metric was the positive predictive value (PPV) at the sensitivity achieved by the medical oncologists with their 3MSQ answers.A total of 74 oncologists answered 3099 3MSQs for 2041 patients with advanced cancer (median age, 62.6 [range, 18-96] years; 1271 women [62.3%]). In this cohort with a 15% prevalence of 3-month mortality and 30% sensitivity for both oncologists and the model, the PPV of oncologists was 34.8% (95% CI, 30.1%-39.5%) and the PPV of the model was 60.0% (95% CI, 53.6%-66.3%). Area under the receiver operating characteristic curve for the model was 81.2% (95% CI, 79.1%-83.3%). The model significantly outperformed the oncologists in short-term mortality.In this prognostic study, the model outperformed oncologists overall and within the breast and gastrointestinal cancer cohorts in predicting 3-month mortality for patients with advanced cancer. These findings suggest that further studies may be useful to examine how model predictions could improve oncologists' prognostic confidence and patient-centered goal-concordant care at the end of life.
A novelly designed protein antagonist confers potent neutralization against SARS-CoV-2 variants of concern
Authors: Panjing Lv, Bing Hu, Rong Hua, Jun Zhang, Haoran Zhang, Zhang Liu, Liqiong Xu, Zhen He, Xiang Li, Ming Guo, Kai Pan, Zhen Zhang, Qili Zeng, Zhi Wu, Li Sun, Meng Guo, Li Zhou, Xiuzhen Xu, Bo Yu, Junqiang Xu, Shuai Yuan, Min Guo, Kun Cai, Yuchen Xia, Yan Li
Journal: Journal of Infection (2022)
<i>BRAF</i> mutation classes and co-occurring mutations in NSCLC.
Authors: Jiaxin Niu, Cynthia A. Flannery, David W. Hall, Jess W. Hoag, Nishitha Therala, Ariane C. Kemkes, Josh Routh, Jean-Paul De La O, Lisa Macera, Snehal Govind Thakkar
Journal: Journal of Clinical Oncology (2022)

9083 Background: Targeted therapy against unique molecular drivers has revolutionized non-small cell lung cancer (NSCLC) treatment. BRAF mutations, present in 2%-5%, have emerged as therapeutic targets, and can be divided into three classes: kinase-activating monomers (class I, V600) or dimers (class II), or kinase-inactivating dimers (class III). Most studies have focused on BRAF V600E NSCLC. Limited clinical data suggest classes II and III may not respond well to chemo- or targeted therapy and tend to have a poorer prognosis. Little is known about co-occurring mutations. This study examines BRAF classes and co-occurring mutations in NSCLC. Methods: Between October 2018 and October 2021, data from 3009 NSCLC Oncotype MAP test results were analyzed. This test utilizes tumor DNA to identify single nucleotide variants, indels, copy number alterations, and select structural variants/fusions by next generation sequencing with a 257 gene panel. Tumor mutational burden and microsatellite instability are also assessed. Pathogenic/likely pathogenic mutations were identified, BRAF mutations assigned to 3 different classes based on current understanding, and associations of other mutated genes with BRAF class examined. Results: Among samples, 133 (4.4%) had BRAF mutations: 30 class I (1%); 42 class II (1.4%); 36 class III (1.2%); and 25 unclassified (0.8%) (Table). Two genes showed associations with BRAF class: STK11 was significantly overrepresented in class II and III, and SETD2 in class I (p&lt;0.05 for both). BRAF class II mutations were further divided into subclasses, IIa (n= 5) and IIb (n= 35); two could not be assigned. The lack of a positive association between KRAS (and NF1) and BRAF class III was unexpected since class III is RAS-dependent while class I and II are RAS-independent. The overrepresentation of STK11 in classes II (with 11/12 events in IIb) and III might explain, at least in part, the poor prognosis relative to class I. By contrast, SETD2 is overrepresented in class I, which might help explain its better response to immunotherapy. Conclusions: For the first time we report the incidence of BRAF mutation classes and associated co-mutations in NSCLC. These associations may help to explain therapeutic outcomes. The impact of coexisting STK11 mutations in class II subclasses warrants further investigation.[Table: see text]
Immunophenotypic correlates and response to first-line pembrolizumab among elderly patients with PD-L1-high (≥ 50%) non–small cell lung cancer.
Authors: Adriana Paula de Castro Barrichello, Joao Victor Machado Alessi, Biagio Ricciuti, Federica Pecci, Victor R. Vaz, Giuseppe Lamberti, Madison M. Turner, Kathleen L. Pfaff, Scott J. Rodig, Mark M. Awad
Journal: Journal of Clinical Oncology (2022)

9054 Background: Older age is associated with increased levels of systemic inflammation and altered immunosurveillance in cancer. Whether aging correlates with a distinct immunophenotype or impacts clinical outcomes to first-line pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) of ≥50% is unclear. Methods: We performed a retrospective analysis of patients with NSCLC. Multiplexed immunofluorescence (mIF) for CD8+, PD-1+, PD-1+CD8+ and FOXP3+ was performed to explore tumor immunophenotype. Clinical outcomes were analyzed on a separate cohort of patients with PD-L1-high (TPS of ≥50%) NSCLC (negative for sensitizing genomic alterations in EGFR and ALK) who received treatment with first-line pembrolizumab. Variables demonstrating a univariate signal of association of p &lt; 0.1 were included in the multivariate model. The results were compared in patients &lt; 80 vs ≥80 years old. Results: Among 541 patients with NSCLCs profiled by mIF, the median age was 67 (28-90). When comparing patients &lt; 80y (n = 497) to ≥80y (n = 44), there was no difference in median CD8+ T cells/mm2 (171 vs 148; p = 0.69), PD-1+ immune cells/mm2 (81.1 vs 87.2; p = 0.95), or PD-1+CD8+ T cells/mm2 (18.0 vs 13.1; p = 0.56). NSCLCs from patients ≥80y had a higher median of intratumoral-associated FOXP3+ T cells/mm2 (63.6 vs 91.1; p = 0.03). In a cohort of 271 patients with PD-L1 ≥50% who received first-line pembrolizumab, baseline clinicopathological characteristics were balanced in the &lt; 80y (n = 225) vs ≥80y (n = 46) groups in terms of sex, tobacco use, Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), histology, presence of potentially targetable driver mutations (KRAS, MET, BRAF, HER2, RET), and PD-L1 TPS distribution (50-89% vs ≥90%). Compared to patients &lt; 80y, patients ≥80y had no difference in objective response rate (ORR 39.1% vs 28.2%; p = 0.22) or median progression-free survival (mPFS 6.0 vs 3.0 months; p = 0.16). However, patients ≥80y had a shorter median overall survival (mOS 25.7 vs 7.6 months; p = 0.02), and this result remained significant after adjusting for ECOG-PS. Among those who experienced disease progression on pembrolizumab, patients ≥80y were significantly less likely to receive any second-line systemic therapy compared to patients &lt; 80y (55.6% vs 30.8%; p = 0.008). Conclusions: In patients with NSCLC and PD-L1 ≥50%, the ORR and mPFS to first-line pembrolizumab were similar between patients &lt; vs ≥80 years old. OS was shorter among patients ≥80y, potentially reflecting lower use of second-line therapy in elderly patients after progression on pembrolizumab. The immunophenotypic correlates of NSCLC in older patients need further investigation.
LGG-23. Cardiac function in children and young adults treated with MEK inhibitors: a single institution retrospecive cohort study
Authors: Nathan Robison, Jennifer Su, Melody Fang, Jemily Malvar, Jondavid Menteer
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: MEK inhibitors (MEKi) have shown efficacy in pediatric low-grade glioma, among other tumors, but have been associated with acute cardiac dysfunction in adults. Cardiac consequences in children are unknown. MATERIAL AND METHODS: We performed a single center retrospective cohort study evaluating cardiac function by echocardiography (echo) in children and young adults &amp;lt;21 years old receiving MEKi at Children’s Hospital Los Angeles between October 2013 and May 2018. Blinded assessment of left ventricular function by fractional shortening (FS) and ejection fraction (EF) was performed on all available echocardiograms obtained before, during, and following therapy, as well as after re-initiation of therapy. RESULTS: Twenty-six patients underwent MEKi therapy with echo follow-up during the study period. Twenty-four of these had complete echo data. Median follow-up was 12 months. Borderline EF (EF 53-57.9%) occurred in 12 (50%) patients; and 3 (12.5%) progressed to abnormal EF (EF &amp;lt;53%). Cardiac dysfunction, when it occurred, was mild (lowest documented EF was 45%, and lowest FS was 24.4%). EF abnormalities typically fluctuated during therapy, resolved off therapy, and recurred with MEKi re-initiation. No clinical or demographic differences were detected between those who maintained normal cardiac function and those who developed borderline or overt cardiac dysfunction. Symptomatic heart failure did not occur. CONCLUSION: In this cohort of children and young adults, MEKi use was associated with a relatively high incidence of borderline decrease in left ventricular function, often of uncertain clinical significance. There was no evidence of permanent cardiac dysfunction. Further evaluation in larger prospective trials is needed.